Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity.
Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity.
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DOI：
10.1210/jc.2016-1990
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发表时间：
2016-11
期刊：
影响因子：
--
通讯作者：
Holterhus PM
中科院分区：
文献类型：
--
作者：
Hornig NC;Ukat M;Schweikert HU;Hiort O;Werner R;Drop SL;Cools M;Hughes IA;Audi L;Ahmed SF;Demiri J;Rodens P;Worch L;Wehner G;Kulle AE;Dunstheimer D;Müller-Roßberg E;Reinehr T;Hadidi AT;Eckstein AK;van der Horst C;Seif C;Siebert R;Ammerpohl O;Holterhus PM
Only approximately 85% of patients with a clinical diagnosis complete androgen insensitivity syndrome and less than 30% with partial androgen insensitivity syndrome can be explained by inactivating mutations in the androgen receptor (AR) gene. The objective of the study was to clarify this discrepancy by in vitro determination of AR transcriptional activity in individuals with disorders of sex development (DSD) and male controls. Quantification of DHT-dependent transcriptional induction of the AR target gene apolipoprotein D (APOD) in cultured genital fibroblasts (GFs) (APOD assay) and next-generation sequencing of the complete coding and noncoding AR locus. The study was conducted at a university hospital endocrine research laboratory. GFs from 169 individuals were studied encompassing control males (n = 68), molecular defined DSD other than androgen insensitivity syndrome (AIS; n = 18), AR mutation-positive AIS (n = 37), and previously undiagnosed DSD including patients with a clinical suspicion of AIS (n = 46). There were no interventions. DHT-dependent APOD expression in cultured GF and AR mutation status in 169 individuals was measured. The APOD assay clearly separated control individuals (healthy males and molecular defined DSD patients other than AIS) from genetically proven AIS (cutoff < 2.3-fold APOD-induction; 100% sensitivity, 93.3% specificity, P < .0001). Of 46 DSD individuals with no AR mutation, 17 (37%) fell below the cutoff, indicating disrupted androgen signaling. AR mutation-positive AIS can be reliably identified by the APOD assay. Its combination with next-generation sequencing of the AR locus uncovered an AR mutation-negative, new class of androgen resistance, which we propose to name AIS type II. Our data support the existence of cellular components outside the AR affecting androgen signaling during sexual differentiation with high clinical relevance. The use of Apolipoprotein D as a biomarker for androgen sensitivity identifies a new type of androgen insensitivity syndrome that is not associated with a mutation in the androgen receptor gene.
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影响因子：
5.3
作者：
Tan, Peck Yean;Chang, Cheng Wei;Cheung, Edwin
通讯作者：
Cheung, Edwin
DOI：
10.1038/nrendo.2014.130
发表时间：
2014-10
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.1
作者：
Hiort, O;Sinnecker, GHG;Kruse, K
通讯作者：
Kruse, K
影响因子：
11.4
作者：
Chng, Kern Rei;Chang, Cheng Wei;Cheung, Edwin
通讯作者：
Cheung, Edwin
影响因子：
5.8
作者：
Holterhus, PM;Bruggenwirth, HT;Brinkmann, AO
通讯作者：
Brinkmann, AO